Antibodies are the principal correlates of immunity to influenza in most studies. Antibodies that bind the hemagglutinin (HA) molecule with high affinity can neutralize virus and inhibit hemagglufinafion in vitro. One of the challenges to inducing durable immunity against influenza is that the neutralizing targets of anti-HA antibodies are peptide loops that exhibit a high degree of plasticity and thus antigenic variability, manifested by antigenic drift on a yearly basis. The structural basis of the antigenicity of the HA molecule has been described in some detail, yet the molecular basis for fundamental features of the influenza antibody response is incompletely understood. The work we propose focuses on detailed molecular and structural studies of the interaction of human monoclonal anfibodies to influenza HI hemagglutinin. The work promises to elucidate fundamental features underlying "original antigenic sin", antibody neutralization "escape" mutations, and the basis of epitope "recycling". The details of this work will be used to construct and test models that can be used to develop new vaccine antigens on a rational basis that induce antibody responses characterized by high affinity, high potency, and a high level of cross-reactivity. RELEVANCE (See instructions): Antibodies are an important part of the immune response to influenza virus, however relatively little is understood about how human antibodies recognize and kill influenza viruses. The work proposed in Project 4 will define in detail how human anfibodies kill various important influenza viruses,' including the 1918 pandemic virus. The information gathered will help up design new vaccines and antibodies for influenza.